FDA Treads Delicate Line Between Safety and Speed

The FDA uses a complex series of procedures to get needed drugs to patients as quickly as possible while ensuring safety. Patricia Keegan, md, oncology staff director in the FDA’s Clinical Trial Design and Analysis Division, walked the audience through several of these procedures at the 89th Annual Meeting of the American Association for Cancer Research.

The standard study procedure for a possible new drug consists of three or four phases of clinical trials that the drug must pass through successfully to win FDA approval. However, special provisions for drugs meant for serious and life-threatening diseases allow these agents to get to market faster.

Standard Clinical Trials Process

Dr. Keegan described the standard series of clinical trials. As she noted, the purpose of the phase I trial is to determine a drug’s dose range and toxicity. Because cancer drugs are generally toxic and because the correct doses are not yet known, phase I trials are usually conducted in people with cancer, in whom the possible benefits help offset the risks.

Once a tolerable dose range has been established, phase II trials determine the drug’s activity. At this stage, researchers may do further exploration of the dose range in patients with measurable disease. Because the goal is to test how well the drug works, researchers need to be able to tell whether the drug is improving or worsening the disease.

When phase II trials demonstrate some effectiveness, Dr. Keegan said, the drug may advance to phase III trials. In order to test the new drug’s safety and effectiveness, these clinical trials compare it with a placebo or standard therapy. Usually, the goal is to show that the new drug works at least as well as no drug at all and as well as or better than existing drugs.

After phase III trials, the company may submit an application to the FDA for approval. In evaluating potential cancer drugs, the FDA typically looks for evidence that the treatment extends the patient’s survival or that it eases symptoms and thereby improves the patient’s well-being.

If approval is granted, the company may conduct a series of phase IV trials after the drug is on the market. These new trials again focus on safety and efficacy, this time in a broader population. The manufacturer can also obtain information on delayed or sustained effects.

Faster Approval Possible

When there is an unusually great need for a drug—for example, when it is meant for a serious or life-threatening disorder for which there is no good existing therapy—the FDA offers three ways to get drugs to patients faster: expedited review, accelerated approval, and fast-track approval.

Expedited Review—In expedited review, also known as subpart E status, the company can apply for approval based on well-executed and well-controlled phase II trials that showed efficacy. In general, the FDA would require phase IV trials for a drug approved under expedited review.

Accelerated Approval—In accelerated approval, the company applies for conditional approval based on the demonstration of meaningful therapeutic benefit over existing therapies, Dr.Keegan said. The FDA might set certain restrictions on the drug to ensure safety and could withdraw approval if those conditions are not followed. As in expedited review, the FDA may require phase IV trials to continue to study the drug after approval.

Fast-Track Approach—This process is meant for drugs that have demonstrated potential to fulfill an unmet medical need. Companies who have applied for fast-track status for a drug can also apply for “rolling application.” This means that the company can submit its marketing application in pieces as each is finished, rather than waiting until the application is complete.

Getting Investigational Drugs to Patients

Dr. Keegan briefly listed a few ways that the FDA is helping patients get expanded access to agents under investigation. One example is the single-patient investigational new drug (IND) application. A researcher can apply for permission to give a specific named patient the investigational drug even though the patient does not meet all of the requirements for joining a clinical trial.

The FDA may allow the patient to receive the drug if three conditions are met: The manufacturer is willing to supply the drug, a physician is willing to administer it, and the patient is willing to take it (as shown by signing a consent form).

Dr. Keegan stressed that drug manufacturers fare best if they stay in close contact with the agency from the very beginning of drug development. The FDA can guide the company with respect to what must be done to get approval. For example, it is important to have a meeting with the FDA before the first IND application is even filed. The agency can advise the company as to what it expects to see in the IND application, and the FDA and the company can iron out problems and come to an agreement on the study end points.

Dr. Keegan explained that these meetings can often be conducted by conference calls or videoconferencing rather than in person. For companies that would like to take advantage of expedited review, accelerated approval, or fast-track approval, staying in close touch with FDA is even more crucial.